DE2124256A1 - Oral antidiabetics - contg dicarboxylic amino acids - Google Patents
Oral antidiabetics - contg dicarboxylic amino acidsInfo
- Publication number
- DE2124256A1 DE2124256A1 DE19712124256 DE2124256A DE2124256A1 DE 2124256 A1 DE2124256 A1 DE 2124256A1 DE 19712124256 DE19712124256 DE 19712124256 DE 2124256 A DE2124256 A DE 2124256A DE 2124256 A1 DE2124256 A1 DE 2124256A1
- Authority
- DE
- Germany
- Prior art keywords
- oral
- acid
- antidiabetic
- oral antidiabetic
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940127017 oral antidiabetic Drugs 0.000 title claims abstract description 16
- 150000001413 amino acids Chemical class 0.000 title abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 23
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960003243 phenformin Drugs 0.000 claims abstract description 13
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960005371 tolbutamide Drugs 0.000 claims abstract description 8
- 150000001767 cationic compounds Chemical class 0.000 claims abstract description 6
- 229910001411 inorganic cation Inorganic materials 0.000 claims abstract description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 4
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract 2
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000004480 active ingredient Substances 0.000 claims description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
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- 150000004283 biguanides Chemical group 0.000 claims description 3
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
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- -1 sulfonyl alcohol Chemical compound 0.000 claims 1
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- 235000001014 amino acid Nutrition 0.000 abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- OZDAOHVKBFBBMZ-UHFFFAOYSA-N 2-aminopentanedioic acid;hydrate Chemical compound O.OC(=O)C(N)CCC(O)=O OZDAOHVKBFBBMZ-UHFFFAOYSA-N 0.000 abstract 1
- 150000002430 hydrocarbons Chemical group 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
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- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 abstract 1
- RPAJSBKBKSSMLJ-DFWYDOINSA-N (2s)-2-aminopentanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CCC(O)=O RPAJSBKBKSSMLJ-DFWYDOINSA-N 0.000 description 10
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 4
- 108090001061 Insulin Proteins 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 239000003629 gastrointestinal hormone Substances 0.000 description 4
- 229940125396 insulin Drugs 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- OANRTGHJSZNHQB-QTNFYWBSSA-L calcium;(2s)-2-aminopentanedioate;hydrochloride Chemical compound Cl.[Ca+2].[O-]C(=O)[C@@H](N)CCC([O-])=O OANRTGHJSZNHQB-QTNFYWBSSA-L 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 210000004051 gastric juice Anatomy 0.000 description 3
- 239000003538 oral antidiabetic agent Substances 0.000 description 3
- 229940123208 Biguanide Drugs 0.000 description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 102100037505 Secretin Human genes 0.000 description 2
- 108010086019 Secretin Proteins 0.000 description 2
- 229940100389 Sulfonylurea Drugs 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- LUUAAIHWKUJNKC-JIZZDEOASA-L calcium;(2s)-2-aminobutanedioate;hydrochloride Chemical compound Cl.[Ca+2].[O-]C(=O)[C@@H](N)CC([O-])=O LUUAAIHWKUJNKC-JIZZDEOASA-L 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- QYOBXHXZJRPWDE-JIZZDEOASA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate;chloride Chemical compound [Mg+2].Cl.[O-]C(=O)[C@@H](N)CC([O-])=O QYOBXHXZJRPWDE-JIZZDEOASA-L 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
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- 238000002360 preparation method Methods 0.000 description 2
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- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- DWHMPBALQYTJFJ-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;hydrochloride Chemical compound Cl.OC(=O)[C@@H](N)CC(O)=O DWHMPBALQYTJFJ-DKWTVANSSA-N 0.000 description 1
- 101800001982 Cholecystokinin Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
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- 239000004472 Lysine Substances 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
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- 229940079920 digestives acid preparations Drugs 0.000 description 1
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000003345 hyperglycaemic effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
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- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 229940073490 sodium glutamate Drugs 0.000 description 1
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- 230000004936 stimulating effect Effects 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/315—Zinc compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Therapeutisches Mittel E ist beschrieben werden, cia gastro-intestinale Hormone (inkretln, Sekretin, Pankreozymin etc.) die Insulinsekretion stimulieren, (E.F.Pfeiffer, Med.Klin. 64, 922 (i969) Selecta XII(1) ?4 ff. (1970), wobei der Wirkungsmechanismus bisher nicht völlig aufgeklärt ist. Die Ausschüttung der gastro-intestinalen Hormone kann durch einen Säurereiz ausgelöst werden, wie zum Beispiel durch Salzsäure und auch in gewissem Maße durch Aminosäuren (E.F.Pfeifrer, Theraplewoche, 18 1228 (1968). Therapeutic agent E is to be described cia gastrointestinal Hormones (incretin, secretin, pancreozymin etc.) stimulate insulin secretion, (E.F. Pfeiffer, Med.Klin. 64, 922 (1969) Selecta XII (1)? 4 ff. (1970), whereby the Mechanism of action has not yet been fully elucidated. The secretion of the gastrointestinal Hormones can be triggered by an acidic stimulus, such as hydrochloric acid and also to a certain extent by amino acids (E.F. Pfeifrer, Theraplewoche, 18 1228 (1968).
Es ist weiterhin bekannt (Stefan Fajans et al., J.clin. Endocrin.It is also known (Stefan Fajans et al., J.clin. Endocrin.
27, 361 (1961), daß Leucin (#- Aminomonocarbonsäure) einen beträchtlichen Anstieg des Plasmainsulins verursacht, während ein solcher Effekt sich mit den anderen essentiellen Aminosäureh nicht erzielen läßt. Weiterhin ist beschrieben (E.F.Pfeiffer, Therapiewoche, 18, 1228 (1968), daß auch Aminosäuren eine -in unterschiedlicher Ausprägung - stimulierende Wirkung auf eine vermehrte Ausschüttung des Insulins haben. Es beinhaltet, daß am wenigsten Leucin stimuliert. über Glutaminsäure (d. Aminodicarbonsäure) wurde (R.Marcus und G.Reavens, Proc.Soc.exp.27, 361 (1961) that leucine (# - aminomonocarboxylic acid) has a considerable Increase in plasma insulin caused while such an effect is with the others essential amino acid can not be achieved. It is also described (E.F. Pfeiffer, Therapiewoche, 18, 1228 (1968) that amino acids also have a different Expression - stimulating effect on an increased release of insulin to have. It implies that the least amount of leucine is stimulated. via glutamic acid (i.e. Aminodicarboxylic acid) (R.Marcus and G.Reavens, Proc.Soc.exp.
Biol. 124, 970-72 (1967) sogar über einen entgegengesetzten Effekt, nämlich über eine hyperglykämische Wirkung berichtet.Biol. 124, 970-72 (1967) even about an opposite effect, namely reported a hyperglycemic effect.
BezUglich der Wirkung von Aminosäuren auf die Magensekretion finden sich in der Literatur ebenfalls widersprechende Angaben.Find out about the effect of amino acids on gastric secretion also contradicting information in the literature.
Aus diesem Grunde wurde dieses Gebiet von H. Melzer et al. neu bearbeitet (Arzneimittelforschung 21, 107-110 (1971). Die Autoren führten aus, daß Natriumglutamat,Glutaminsäurehydrochlorid, Lysin, ß-Alanin und ein Säurehydrolysat aus Gelatine bezüglich ihrer säurelockenden Aktivität unwirksam sind, sie unterscheiden sich nicht signifikant vom Placebo.For this reason, this area was proposed by H. Melzer et al. reworked (Arzneimittelforschung 21, 107-110 (1971). The authors stated that sodium glutamate, glutamic acid hydrochloride, Lysine, ß-alanine and an acid hydrolyzate from gelatin with regard to their acidic attractiveness Activity are ineffective; they are not significantly different from placebo.
Zusammenfassend ergibt sich aus dieser Literatur, daß b.-sonders die Gruppe der sauren Aminosäuren mit einz isoelektrischen Punkt-Bereich von 2,5 bis 4. wie er für die d- Aminodicarbonsäure und somit auch fUr die Glutaminsäure charakteristisch ist, als Säurelocker unbrauchbar sind.In summary, it can be seen from this literature that b.-sonders the Group of acidic amino acids with a single isoelectric point range from 2.5 to 4. as it is characteristic of d-aminodicarboxylic acid and thus also of glutamic acid is useless as acid looseners.
Der Erfindung liegt die Aufgabe zugrunde, ein wirksames, vera trägliches und in der Herstellung einfaches orales Antidiabebeticum als Wirkstoff eine R - Aminodicarbonsäure der allgemeinen Formel: wobei X einen geradkettigen oder verzweigten Kohlen\wasserstoffrest mit 1 bis 4 C-Atomen bedeutet, vollkommen oder teilweise in Form eines physiologisch verträglichen säureadditionnssaises vorliegend, enthält.The invention is based on the object of an effective, vera tolerable and easy to manufacture oral antidiabetic agent as an active ingredient an R - aminodicarboxylic acid of the general formula: where X denotes a straight-chain or branched hydrocarbon radical with 1 to 4 carbon atoms, completely or partially in the form of a physiologically compatible acid addition acid.
Überraschenderweise hat sich gezeigt, daß mit dem erfindungsgesüßen Antidiabeticum offenbar der Mechanismus der gastrointestinalen Hormone in Gang gesetzt wird. Man erzielt so in einfacher Weise durch orale Verabfolgung eines gut verträglichen, sowie preisgunstigen und stabilen Aminodicarbonsäureprärarates einen hervorrägenden Effekt. Schon die tägliche ein- bis zweimalige orale Verabreichung eines Präparates, das 250 bis 500 Ig Clutaminsäurehydrochlorid enthält, bewirkt bei nicht insulinpflichtigen Diabetikern in großem Umfang eine Normalisierung des Blutzuckerspiegels.Surprisingly, it has been shown that with the inventive sweetness Antidiabetic apparently set in motion the mechanism of gastrointestinal hormones will. This is achieved in a simple manner by oral administration of a well-tolerated, as well as inexpensive and stable aminodicarboxylic acid preparations an excellent one Effect. Even the oral administration of a preparation once or twice a day, which contains 250 to 500 Ig clutamic acid hydrochloride, affects those who do not require insulin Diabetics to a large extent normalize blood sugar levels.
Das erfindungsgemäße Antidiabeticum hat weiterhin den Vorteil, daß ein hypoglykämisches Abgleiten der.Patienten bei dieser Therapie ausgeschlossen ist. Die intestinalen Hormone zeigen gegenüber Normalpersonen keinen Glucose-regulierenden Effekt.The antidiabetic according to the invention also has the advantage that a hypoglycemic sliding of the patients with this therapy excluded is. Compared to normal persons, the intestinal hormones do not show any glucose-regulating effects Effect.
Sie sind wirksam bei subkilnischem Diabetes und bei Altersdiabetes.They are effective in sub-clinical and adult diabetes.
Gegenilber juvenilen Diabetikern wirken sie nur in geringfügigem Masse (J.Raptis et al. DMW 93, 2420 (1968).They have only a minor effect on juvenile diabetics (J. Raptis et al. DMW 93, 2420 (1968).
Ein weiterer Vorteil der Behandlung mit dem erfindungsgemässen Antidiabetioum über den Mechanismus intestinaler Mormone besteht darin, dass Altersdiabetiker, die beispielsweise nicht mehr auf Sulfonylharnstoffe, wie Tolbutamid, ansprechen, noch mit einer Insulinausschüttung durch Sekretininjektionen reagieren.Another advantage of the treatment with the antidiabetic agent according to the invention about the mechanism of intestinal Mormons is that elderly diabetics, who no longer respond to sulfonylureas such as tolbutamide, for example, react with a release of insulin through secretin injections.
Gemäss einer weiteren Ausbildung der Erfindung kann das Antidiabeticum in Kombination mit oralen Antidiabeticavorliegen, so z.B.According to a further embodiment of the invention, the antidiabetic in combination with oral antidiabetic agents, e.g.
Kombinationen von d-Aminodicarbonsäuren, vorzugsweise Glutaminsäurehydrochlorid, mit den genannten Stoffen. Diese Kombinationen haben günstige Wirkungen, da auf diese Weise die sonst notwendige Dosierung der oralen Antidiabetica herabgesetzt werden kann und somit bekannt gewordene Nebenwirkungen der ß-cytotropen Substanzen, wie z.B der bulfonylharnstoffe und ganz allgemein Unverträglichkeitsreaktionen der oralen Antidiabetica auezuschalten sind. Es tritt hier durch die Verwendung von #- Aminodicarbonsäuren, vorzugsweise Glutaminsäurehydrochlorid, in einfacher Weise durch per os Applikation ein gleichfalls potenzierender Effekt gegenüber oralen Antidiabeitca ein. Besonders günstig wirken sich Kombinationen der D-Aminodicarbonsäuren, z.B. des Glutaminsäurehydrochloride, mit oralen Antidiabetica der Biguanidgruppe aus, die insbesondere die periphere Glucose-Utilisation begünstigen. Auch hier zeigte sich der potenzierende Effekt, beispielsweise gegenüber Phenformin.Combinations of d-aminodicarboxylic acids, preferably glutamic acid hydrochloride, with the substances mentioned. These combinations have beneficial effects as on in this way the otherwise necessary dosage of oral antidiabetic agents is reduced and thus known side effects of the ß-cytotropic substances, such as the bulfonylureas and generally intolerance reactions of the oral antidiabetics are to be switched off. It occurs here through the use of # - Aminodicarboxylic acids, preferably glutamic acid hydrochloride, in a simple manner Oral application also has a potentiating effect compared to oral application Antidiabeitca a. Combinations of D-aminodicarboxylic acids have a particularly beneficial effect, e.g. of glutamic acid hydrochloride, with oral antidiabetics of the biguanide group which particularly favor peripheral glucose utilization. Also showed here the potentiating effect, for example compared to phenformin.
Gemäss einer weiteren Ausbildung der Erfindung können die freien Carboxylgruppen der #- Aminodicarbonsäuren vollkommen oder teilweise durch physiologisch verträgliche anorganische kationen gebunden sein, so z.B. mit Ca-Ionen für den Transport und eine komplette Insulinsekretion. Die den Erfindungsgemässen Wirkstoffen zugrunde liegenden α-Aminodicarbonsäuren sind auch in Form der Säureadditionssalze befähigt, Kationen zu binden, Auf dieeem Wege ist somit die Möglichkeit gegeben, die fir eine Diabetesbehandlung als günstig befundenen Kationen in die Präparat ionen einzusetzen, so beispielsweise : Calciumaspartathydrochlorid, Calciumglutamathydrochlorid, Magnesiumaspartathydrochlorid, Magnesiumgltamathydrochlard.According to a further embodiment of the invention, the free carboxyl groups the # - aminodicarboxylic acids completely or partially through physiologically compatible inorganic cations be bound, e.g. with Ca ions for transport and complete insulin secretion. The active ingredients according to the invention are based lying α-aminodicarboxylic acids are also in the form of acid addition salts capable of binding cations, in this way the possibility is given the cations found to be beneficial for diabetes treatment in the preparation to use ions, for example: calcium aspartate hydrochloride, calcium glutamate hydrochloride, Magnesium aspartate hydrochloride, magnesium gltamate hydrochloride.
Die nachfolgenden Beispiele erläutern einige Dosierungsmögliohkeiten und Anwendungsformen, ohne damit den Umfang der Patent-Anmeldung zu limitieren.The following examples illustrate some dosage options and application forms, without thereby limiting the scope of the patent application.
Beispiel 1 Es werden 25o bzw. 500 mg Glutaminsäurehydrochlorid gemeinsam mit Tablettierungemitteln, wie z.B. Maisstärke, Tablettierungshilfsmitteln, Stearinsäure, Talkum oder dgl. in üblicher Weise zu Kernen verpreest und sprühdragiert. Die Kerne sind so be -schaffen, dass sie im Magensaft zerfallen.Example 1 There are 250 or 500 mg of glutamic acid hydrochloride together with tableting agents, such as corn starch, tableting auxiliaries, stearic acid, Talc or the like pressed into cores in the usual way and spray coated. The cores are so made that they disintegrate in gastric juice.
Beispiel 2 Gemäss Beispiel 1 werden verarbeitet 250 bzw. Soo mg Asparaginsäurehydrochlorid.Example 2 According to Example 1, 250 or so mg of aspartic acid hydrochloride are processed.
Beispiels 3 Gemäss beispiel 1 werden verarbeitet 500 mg Oalciumaspartathydroohlorid.Example 3 According to example 1, 500 mg of calcium aspartate hydrochloride are processed.
Beispiel 4 Geaäss beispiel 1 werden verarbeitet 500 mg Calciumglutamathydrochlorid.Example 4 According to Example 1, 500 mg of calcium glutamate hydrochloride are processed.
Beispiel 5 betrifft die Kombination mit dem Biguanid t Phenformin.Example 5 relates to the combination with the biguanide t phenformin.
Es werden hierfür 500 mg Glutaminsäurehydrochlorid mit 20 mg Phenformin gemeinsam mit Tablettierungemitteln gemäss Beispiel 1 verarbeitet.For this purpose, 500 mg of glutamic acid hydrochloride with 20 mg of phenformin are used processed together with tabletting agents according to Example 1.
Gesondert werden 20 mg Phenformin mit Tablettierungehilfe -mitteln zu Tabletten verpresst und anschliessend mit einem Magensaft - resistenten Überzug versehen.Separately, 20 mg of phenformin are used with tableting aids Compressed into tablets and then coated with a gastric juice-resistant coating Mistake.
Beide Presslinge werden in eine Kapsel gefüllt.Both pellets are filled into a capsule.
Beispiel 6 Ee wird gemäss 3eispiel 5 gearbeitet und anstelle des Glutaminsäurehydrochlorids 500 mg Calciumglutamathydrochlorid eingesetzt.Example 6 Ee is carried out according to Example 5 and instead of glutamic acid hydrochloride 500 mg calcium glutamate hydrochloride used.
Beispiel 7 Ee wird gemäss Beispiel 5 gearbeitet und anstelle des Glutaminsäurehydrochlorids 500 mg Magnesiumaspartathydrochlorid eingesetzt.Example 7 Ee is carried out according to Example 5 and instead of glutamic acid hydrochloride 500 mg magnesium aspartate hydrochloride used.
Beispiel 8 betrifft die Kombination mit dem Sulfonylharnstoff Tolbutamid und dem Biguanid Phenformin.Example 8 relates to the combination with the sulfonylurea tolbutamide and the biguanide phenformin.
Es werden hierfür 400 mg Glutaminsäurehydrochlorid' 250 mg Tolbutamid und 20 mg Phenformin in Presslingen verarbeitet, die lit einer Magensaft-löslichen Uberzug versehen sind; ein weiterer Presaling enthält 20 mg Phenformin und wird mit einer Magensaftresistenten Überzug verschen. Beide Presslinge werden geneinsam in eine Kapsel gefüllt.There are 400 mg of glutamic acid hydrochloride '250 mg of tolbutamide and 20 mg of phenformin processed in pellets, which lit a gastric juice-soluble Are provided with a coating; another presaling contains 20 mg of phenformin and will give away with an enteric coating. Both pellets are made together filled in a capsule.
Beispiel 9 betrifft die Kombination mit Tolbutamid und Phenformin.Example 9 relates to the combination with tolbutamide and phenformin.
Pressling 1 enthält als Wirkstoff : 500 mg Glutaminsäurehydrochlorid und 20 mg Phenformin. Der Pressling wird mit einem Magensaft-löslichen Überzug sprühdragiert.Pellet 1 contains as active ingredient: 500 mg glutamic acid hydrochloride and 20 mg of phenformin. The pellet is spray-coated with a gastric juice-soluble coating.
Pressling 2 enthält als Wirkstoff : 250 mg Tolbutamid. Der Preseling erhält keinen Überzug.Pellet 2 contains as active ingredient: 250 mg tolbutamide. The preseling does not receive a coating.
Pressling 3 enthält als Wirkstoff : 20 mg Phenformin. Der Pressling wird mit einem Magensaft-resistenten Überzug verschen.Pellet 3 contains as active ingredient: 20 mg phenformin. The pellet is given away with a gastric juice-resistant coating.
Die drei Presslinge werden gemeinsam in eine Kapsel gefüllt.The three pellets are put into a capsule together.
Claims (17)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712124256 DE2124256A1 (en) | 1971-05-15 | 1971-05-15 | Oral antidiabetics - contg dicarboxylic amino acids |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19712124256 DE2124256A1 (en) | 1971-05-15 | 1971-05-15 | Oral antidiabetics - contg dicarboxylic amino acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2124256A1 true DE2124256A1 (en) | 1972-11-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19712124256 Pending DE2124256A1 (en) | 1971-05-15 | 1971-05-15 | Oral antidiabetics - contg dicarboxylic amino acids |
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| Country | Link |
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| DE (1) | DE2124256A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999055320A1 (en) * | 1998-04-29 | 1999-11-04 | Sumitomo Pharmaceuticals Co., Ltd. | Oral formulation comprising biguanide and an organic acid |
| WO2000012097A1 (en) * | 1998-08-31 | 2000-03-09 | Andrx Pharmaceuticals, Inc. | Controlled release tablet comprising a hypoglycemic drug and an antihyperglycemic drug |
| US6495162B2 (en) | 1998-03-20 | 2002-12-17 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
-
1971
- 1971-05-15 DE DE19712124256 patent/DE2124256A1/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6495162B2 (en) | 1998-03-20 | 2002-12-17 | Andrx Pharmaceuticals, Inc. | Controlled release oral tablet having a unitary core |
| US7919116B2 (en) | 1998-03-20 | 2011-04-05 | Andrx Labs, Llc | Controlled release metformin formulations |
| US8475841B2 (en) | 1998-03-20 | 2013-07-02 | Andrx Labs, Llc | Controlled release metformin formulations |
| WO1999055320A1 (en) * | 1998-04-29 | 1999-11-04 | Sumitomo Pharmaceuticals Co., Ltd. | Oral formulation comprising biguanide and an organic acid |
| US6517870B1 (en) | 1998-04-29 | 2003-02-11 | Sumitomo Pharmaceuticals Company, Limited | Oral formulation comprising biguanide and an organic acid |
| WO2000012097A1 (en) * | 1998-08-31 | 2000-03-09 | Andrx Pharmaceuticals, Inc. | Controlled release tablet comprising a hypoglycemic drug and an antihyperglycemic drug |
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